Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor

Sci Adv. 2019 May 22;5(5):eaav3660. doi: 10.1126/sciadv.aav3660. eCollection 2019 May.

Abstract

Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931-induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS-wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Separation
  • Cell Survival
  • Centrosome / drug effects
  • Chromosome Aberrations / drug effects
  • Computational Biology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred BALB C
  • Mitosis / drug effects
  • Models, Animal
  • Mutation
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / drug therapy
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Proteomics
  • Pyrazolones / pharmacology*
  • Pyrimidines / pharmacology*
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Pyrazolones
  • Pyrimidines
  • CDC7 protein, human
  • Protein Serine-Threonine Kinases
  • simurosertib